A calcium channel blocker (CCB) is a chemical that disrupts the movement of calcium (Ca2+) through calcium channels.[1] Calcium channel blockers are used as antihypertensive drugs, i.e. as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients.[2] Calcium channel blockers are also frequently used to alter heart rate, to prevent cerebral vasospasm, and to reduce chest pain caused by angina pectoris. One type of calcium channel blocker is used experimentally to prevent migraine, and another one is used as a powerful painkiller.

Despite their effectiveness, CCB's often have a high mortality rate over extended periods of use, and have been known to have multiple side effects.[3] Potential major risks however were mainly found to be associated with short-acting CCBs.[4]

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In the body's tissues, the concentration of calcium ions (Ca2+) outside of cells is normally about tenthousandfold higher than the concentration inside of cells. Embedded in the membrane of some cells are calcium channels. When these cells receive a certain signal, the channels open, letting calcium rush into the cell. The resulting increase in intracellular calcium has different effects in different types of cells. Calcium channel blockers prevent or reduce the opening of these channels and thereby reduce these effects.

There are several types of calcium channels, and a number of classes of calcium channel blockers, but almost all of them preferentially or exclusively block the L-typevoltage-gated calcium channel.[5]

by acting on cardiac muscles (myocardium), they reduce the force of contraction of the heart

by slowing down the conduction of electrical activity within the heart, they slow down the heart beat.

Since blood pressure is determined by cardiac output and peripheral resistance, CCBs reduce blood pressure. With relatively low blood pressure, the afterload on the heart decreases; this decreases how hard the heart must work to eject blood into the aorta, and so the amount of oxygen required by the heart decreases accordingly. This can help ameliorate symptoms of ischaemic heart disease such as angina pectoris.

Reducing the force of contraction of the myocardium is known as the negative inotropic effect of calcium channel blockers. Slowing down the conduction of electrical activity within the heart, by blocking the calcium channel during the plateau phase of the action potential of the heart (see: cardiac action potential), results in a negative chronotropic effect, or a lowering of heart rate. This can increase the potential for heart block. The negative chronotropic effects of calcium channel blockers make them a commonly used class of agents in individuals with atrial fibrillation or flutter in whom control of the heart rate is generally a goal. Negative chronotropy can be beneficial when treating a variety of disease processes because lower heart rates represent lower cardiac oxygen requirements. Elevated heart rate can result in significantly higher "cardiac work," which can result in symptoms of angina.

The class of CCBs known as dihydropyridines mainly affect arterial vascular smooth muscle and lower blood pressure by causing vasodilation. The phenylalkylamine class of CCBs mainly affect the cells of the heart and have negative inotropic and negative chronotropic effects. The benzothiazepine class of CCBs combine effects of the other two classes.

It is because of the negative inotropic effects that the nondihydropyridine calcium channel blockers should be avoided (or used with caution) in individuals with cardiomyopathy.[6]

Unlike beta blockers, calcium channel blockers do not decrease the responsiveness of the heart to input from the sympathetic nervous system. Since moment-to-moment blood pressure regulation is carried out by the sympathetic nervous system (via the baroreceptor reflex), calcium channel blockers allow blood pressure to be maintained more effectively than do beta blockers. However, because dihydropyridine calcium channel blockers result in a decrease in blood pressure, the baroreceptor reflex often initiates a reflexive increase in sympathetic activity leading to increased heart rate and contractility.

Dihydropyridine calcium channel blockers are derived from the molecule dihydropyridine and often used to reduce systemic vascular resistance and arterial pressure, but are not used to treat angina (with the exception of amlodipine, nicardipine, and nifedipine, which carry an indication to treat chronic stable angina as well as vasospastic angina) because the vasodilation and hypotension can lead to reflex tachycardia. Dihydropiridine calcium channel blockers can worsen proteinuria in patients with nephropathy.[8]

Phenylalkylamine calcium channel blockers are relatively selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, and are often used to treat angina. They have minimal vasodilatory effects compared with dihydropyridines and therefore cause less reflex tachycardia, making it appealing for treatment of angina, where tachycardia can be the most significant contributor to the heart's need for oxygen. Therefore, as vasodilation is minimal with the phenylalkylamines, the major mechanism of action is causing negative inotropy. Phenylalkylamines are thought to access calcium channels from the intracellular side, although the evidence is somewhat mixed.[9]

Benzothiazepine calcium channel blockers belong to the benzothiazepine class of compounds and are an intermediate class between phenylalkylamine and dihydropyridines in their selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines.

Ziconotide, a peptide compound derived from the omega-conotoxin, is a selective N-type calcium channel blocker that has potent analgesic properties that are equivalent to approximate 1,000 times that of morphine. It must be delivered via the intrathecal (directly into the cerebrospinal fluid) route via an intrathecal infusion pump.

Mild CCB toxicity is treated with supportive care. Non-dihydropyridine CCB may produce profound toxicity and early decontamination, especially for slow release agents, is essential. For severe overdoses, treatment usually includes close monitoring of vital signs and the addition of vasopressive agents and intravenous fluids for blood pressure support. IV calcium gluconate (or calcium chloride if a central line is available) and atropine are first-line therapies. If the time of the overdose is known and presentation is within two hours of ingestion, activated charcoal, gastric lavage, and polyethylene glycol may be used to decontaminate the gut. Efforts for gut decontamination may be extended to within 8 hours of ingestion with extended release preparations.

Hyperinsulinemia-euglycemia (HIE) therapy has emerged as a viable form of treatment. Although the mechanism is unclear, it has been hypothesized that increased insulin mobilizes glucose from peripheral tissues to serve as an alternative fuel source for the heart (the heart mainly relies on oxidation of fatty acids). Theoretical treatment with lipid emulsion therapy has been considered in severe cases, but is not yet standard of care.

Caution should be taken when using verapamil with a Beta blocker due to the risk of severe bradycardia. If unsuccessful, ventricular pacing should be used.[12]